WO2016091997A1 - Procédé de fabrication d'idalopirdine - Google Patents

Procédé de fabrication d'idalopirdine Download PDF

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Publication number
WO2016091997A1
WO2016091997A1 PCT/EP2015/079209 EP2015079209W WO2016091997A1 WO 2016091997 A1 WO2016091997 A1 WO 2016091997A1 EP 2015079209 W EP2015079209 W EP 2015079209W WO 2016091997 A1 WO2016091997 A1 WO 2016091997A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mixture
fluoro
solvent
catalyst
Prior art date
Application number
PCT/EP2015/079209
Other languages
English (en)
Inventor
Mikkel Fog JACOBSEN
Ole Nielsen
Original Assignee
H. Lundbeck A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU2015359347A priority Critical patent/AU2015359347A1/en
Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority to JP2017531139A priority patent/JP2017537128A/ja
Priority to RU2017120216A priority patent/RU2017120216A/ru
Priority to MX2017007510A priority patent/MX2017007510A/es
Priority to CA2968770A priority patent/CA2968770A1/fr
Priority to KR1020177015206A priority patent/KR20170093821A/ko
Priority to SG11201704523WA priority patent/SG11201704523WA/en
Priority to BR112017012021A priority patent/BR112017012021A2/pt
Priority to EP15821029.4A priority patent/EP3230265A1/fr
Priority to CN201580065028.6A priority patent/CN107001266A/zh
Publication of WO2016091997A1 publication Critical patent/WO2016091997A1/fr
Priority to IL252471A priority patent/IL252471A0/en
Priority to CONC2017/0005357A priority patent/CO2017005357A2/es

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • the present invention relates to the preparation of N-(2-(6-fluoro-lH-indol-3-yl)-ethyl)- 3-(2,2,3,3-tetrafluoropropoxy)-benzylamine, INN-name idalopirdine, and pharmaceutically acceptable salts thereof.
  • N-(2-(6-fiuoro-lH-indol-3-yl)-ethyl)-3-(2,2,3,3-tetrafluoropropoxy)-benzylamine is a potent and selective 5-HT 6 receptor antagonist which is currently in clinical development. Its chemical structure is depicted below as Com ound (I).
  • This method of manufacture comprises the steps
  • WO2011/076212 further discloses 2-(6-fluoro-lH-indol-3-yl)ethylamine hydrogen L-(+)-tartrate (the 1 :1 salt of 2-(6-fluoro-lH-indol-3-yl)ethylamine and L-(+)-tartaric acid) as well as a process for the purification of 2-(6-fluoro-lH-indol-3-yl)ethylamine comprising the steps of:
  • DMF N,N-dimethylformamide
  • MeOH is methanol.
  • THF is tetrahydrofuran.
  • TCE 2,2,2-trichloroethanol
  • i-PrOH is 2-propanol (isopropyl alcohol).
  • RaNi'VRaney nickel is an activated nickel catalyst which is optionally doped with another metal and that comes in different particle sizes and forms
  • Cyanide source is KCN, NaCN, or other agents which release the CN “ anion.
  • DI is distilled or ultra-pure.
  • M is molar
  • v/v volume per volume
  • HPLC high pressure liquid chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • Pd/C is palladium on charcoal.
  • Platinum/C is platinum on charcoal.
  • Rh/C is rhodium on charcoal.
  • Pore/Alumina is rhodium on aluminium oxide.
  • Ni/Silica-alumina is nickel on a mixture of silicon oxide and aluminium oxide
  • PRICATTM is the trademark for a series of supported nickel catalysts on silica with/without added promotors, from Johnson Matthey Process Technologies.
  • NMP N-methylpyrrolidinone.
  • DMF-DMA N,N-dimethylformamide dimethyl acetal.
  • EDG is ethylene glycol
  • nickel catalyst refers to catalysts comprising nickel or nickel oxides or mixtures thereof.
  • embodiment of the invention is disclosed a process for the preparation of Compound (IV)
  • the nickel catalyst is supported on silica or alumina.
  • the supported nickel catalyst is selected from the group comprising PRICAT 55/5P and PRICAT 62/15P.
  • the alcoholic solvent is methanol, ethanol or 2-propanol.
  • the hydrogenation is run at a pressure from approx. 2 to approx. 10 bar, more particularly from approx. 2 to approx. 6 bar and most particularly from approx. 2 to approx. 4 bar.
  • the hydrogenation is run at a temperature from about 40 °C to about 70 °C, more particularly from about 50 °C to about 60 °C.
  • the hydro genation is run with a loading from about 8 % to about 31 % (w/w) supported nickel catalyst relative to (6-fluoro- lH-indol-3-yl)acetonitrile.
  • sodium borohydride is used as the reducing agent for the reduction to Compound I.
  • Compound (XIII) is reacted in DMF or NMP as solvent. In a more particular embodiment Compound (XIII) is converted to Compound (XI) using DMF- DMA.
  • Compound (XI) is reduced to Compound (X) using Raney nickel or palladium on charcoal as catalyst. In a more particular Compound (XI) is reduced to Compound (X) using hydrazine or hydrogen as reductant.
  • Compound (I) forms pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. Such salts include the pharmaceutically acceptable salts listed in Berge, S. M.et al., J. Pharm. Sci. 1977, 66, 1-19 which are known to the skilled artisan. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and the like.
  • Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
  • Such pharmaceutically acceptable salts thus include chloride, bromide, iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate, phenylbutyrate, a-hydroxybutyrate, butyne-l ,4-dicarboxylate, hexyne-1 , 4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptarioate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, oxalate, phthalate, teraphthalate, propiolate, propionate, phen
  • the mixture from reactor A (DEM, water, formic acid, formaldehyde and ethanol at about 20 °C) was added drop-wise to reactor B while keeping the temperature at 2-8 °C.
  • the reaction mixture was stirred for additional 10 min at 2-8 °C.
  • the reaction mixture was slowly warmed to approx. 40 °C over a 1 h period.
  • the reaction mixture was stirred at approx. 40 °C for an additional 1 h.
  • the reaction mixture was cooled to about 20°C.
  • a 250 L reactor was charged with approx. 40% aq. dimethylamine (35.7 kg, 317 mol) at approx. 17 °C under an inert atmosphere.
  • the mixture was cooled to approx. 4.5 °C and glacial acetic acid (43.4 kg, 723 mol) was added dropwise over 140 min while maintaining the temperature at approx. 15°C.
  • 37% aqueous formaldehyde 25.9 kg, 319 mol
  • reaction was exothermic and reached a final temperature of approx. 40 °C, and it was then cooled down to approx. 20°C.
  • the reaction solution was slowly added to a 650 L reactor previously charged with aq. NaOH (3 M) over a period of approx. 40 min.
  • the formed suspension was stirred for approx. 40 min while keeping the temperature between 5 to 20 °C.
  • the precipitate was filtered from solution, washed with water on the filter, and dried at approx. 50°C to afford Compound (II) (45.4 kg, 81%).
  • the mixture was hydrogenated at 4 bar and at the specified temperature for the specified time.
  • the reaction mixture was analysed directly by LC-MS.
  • DPPF l, -Bis(diphenylphosphino)ferrocene, cas number: 12150-46-8.
  • Tris(triphenylphosphine)ruthenium(II) dichloride cas number 15529-49-4.
  • Tris(triphenylphosprtine)rhodiutri(I) carbonyl hydride cas number 17185-29-4.
  • Example 7 Screening of rhodium, platinum and nickel catalysts
  • PRICAT type 55/5P catalyst (14.0 kg) was charged to a reactor followed by charging of a solution of Compound (III) (46.3 kg, 266 mol) in isopropanol (76.4 kg). Then isopropanol (106 L) and aq. ammonia (302 L, 25%) was charged. The mixture was transferred to a steel autoclave under nitrogen, using extra isopropanol (92 L) for washing of reactor. The autoclave was evacuated and then pressurized with hydrogen gas to 3 bar. The content was heated to 55 °C and hydrogenated at 3 bar hydrogen for 48 h. The content was cooled to 25 °C, and the autoclave was purged with nitrogen gas, and the content filtered on a pressure nutsch filter. The filter was washed with isopropanol (2 x 145 L). This yielded a solution of Compound (IV).
  • the formed suspension was stirred at 60 °C for 3 h, and cooled over a period of 3 h to 25 °C.
  • the suspension was filtered on a pressure nutsch filter, and the filter cake was washed twice with a mixture of isopropanol (170 L), ethyl acetate (78 kg) and water (17 L).
  • the filter cake was broken up and dried on trays in a vacuum oven at 60 °C for 5 days to yield Compound (V) (163 kg, 94%) as an off-white solid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Procédé pour la préparation d'idalopirdine et de ses sels pharmaceutiquement acceptables.
PCT/EP2015/079209 2014-12-12 2015-12-10 Procédé de fabrication d'idalopirdine WO2016091997A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
KR1020177015206A KR20170093821A (ko) 2014-12-12 2015-12-10 이달로피르딘의 제조 방법
JP2017531139A JP2017537128A (ja) 2014-12-12 2015-12-10 イダロピルジンの製造の方法
RU2017120216A RU2017120216A (ru) 2014-12-12 2015-12-10 Способ производства идалопирдина
MX2017007510A MX2017007510A (es) 2014-12-12 2015-12-10 Un proceso para la fabricacion de idalopirdina.
CA2968770A CA2968770A1 (fr) 2014-12-12 2015-12-10 Procede de fabrication d'idalopirdine
AU2015359347A AU2015359347A1 (en) 2014-12-12 2015-12-10 A process for the manufacture of idalopirdine
SG11201704523WA SG11201704523WA (en) 2014-12-12 2015-12-10 A process for the manufacture of idalopirdine
CN201580065028.6A CN107001266A (zh) 2014-12-12 2015-12-10 用于生产艾达鲁吡啶的方法
EP15821029.4A EP3230265A1 (fr) 2014-12-12 2015-12-10 Procédé de fabrication d'idalopirdine
BR112017012021A BR112017012021A2 (pt) 2014-12-12 2015-12-10 um processo para a fabricação de idalopirdina
IL252471A IL252471A0 (en) 2014-12-12 2017-05-23 A process for the production of idalopyridine
CONC2017/0005357A CO2017005357A2 (es) 2014-12-12 2017-05-26 Un proceso para la fabricación de idalopirdina

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA201400721 2014-12-12
DK201400721 2014-12-12

Publications (1)

Publication Number Publication Date
WO2016091997A1 true WO2016091997A1 (fr) 2016-06-16

Family

ID=55077474

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2015/079209 WO2016091997A1 (fr) 2014-12-12 2015-12-10 Procédé de fabrication d'idalopirdine

Country Status (5)

Country Link
US (1) US20160168089A1 (fr)
AR (1) AR102980A1 (fr)
SG (1) SG11201704523WA (fr)
TW (1) TW201630881A (fr)
WO (1) WO2016091997A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017174691A1 (fr) 2016-04-08 2017-10-12 H. Lundbeck A/S Procédé de fabrication d'idalopirdine par hydrogénation d'une imine
WO2018013686A1 (fr) * 2016-07-12 2018-01-18 Concert Pharmaceuticals, Inc. Idalopirdine deutérée
US10196363B2 (en) 2014-12-12 2019-02-05 Japan Tobacco Inc. Dihydropyrimidin-2-one compounds and medical use thereof
US10899717B2 (en) 2018-02-28 2021-01-26 Japan Tobacco Inc. 4-methyldihydropyrimidinone compounds and pharmaceutical use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3042685A (en) * 1962-07-03 Process of making g-fluoro tryptamine
US7157488B2 (en) 2001-03-29 2007-01-02 Eli Lilly And Company N-(2-Arylethyl) benzylamines as antagonists of the 5-HT6 receptor
WO2011076212A2 (fr) 2009-12-23 2011-06-30 H. Lundbeck A/S Procédés de fabrication d'un principe pharmaceutiquement actif

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0807631B1 (fr) * 1996-05-15 2003-03-12 Sankyo Company Limited Composés tricycliques à activité fongicide, leur préparation et leur application
US7022645B2 (en) * 2003-08-04 2006-04-04 Catalytic Distillation Technologies Ni hydrogenation catalysts, manufacture and use
AR065804A1 (es) * 2007-03-23 2009-07-01 Smithkline Beecham Corp Compuesto de indol carboxamida, composicion farmaceutica que lo comprende y uso de dicho compuesto para preparar un medicamento
JP5373764B2 (ja) * 2007-04-16 2013-12-18 マリンクロッド エルエルシー 触媒性水素転移反応を使用する新規なオピエート還元

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3042685A (en) * 1962-07-03 Process of making g-fluoro tryptamine
US7157488B2 (en) 2001-03-29 2007-01-02 Eli Lilly And Company N-(2-Arylethyl) benzylamines as antagonists of the 5-HT6 receptor
WO2011076212A2 (fr) 2009-12-23 2011-06-30 H. Lundbeck A/S Procédés de fabrication d'un principe pharmaceutiquement actif

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BERGE, S. M. ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
BOINI, S. ET AL., ORG. PROC. RES. DEV., vol. 10, 2006, pages 1205 - 12LL
BOINI, S. ET AL.: "Development of a Manufacturing Process for 1-(1-Pyridin-2-yl methyl-piperidin-4-yl)-1H-indole: A Key Intermediate for Protein Kinase C Inhibitor LY317615", ORG. PROC. RES. DEV., vol. 10, 2006, pages 1205 - 1211, XP055008625, DOI: 10.1021/op060068k *
GILLMORE, A. T. ET AL., ORG. PROC. RES. DEV., vol. 16, 2012, pages 1897 - 1904
GILLMORE, A. T. ET AL.: "Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor", ORG. PROC. RES. DEV., vol. 16, 2012, pages 1897 - 1904, XP055250298, DOI: 10.1021/op200238p *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10196363B2 (en) 2014-12-12 2019-02-05 Japan Tobacco Inc. Dihydropyrimidin-2-one compounds and medical use thereof
WO2017174691A1 (fr) 2016-04-08 2017-10-12 H. Lundbeck A/S Procédé de fabrication d'idalopirdine par hydrogénation d'une imine
US9975850B2 (en) 2016-04-08 2018-05-22 H. Lundbeck A/S Process for the manufacture of idalopirdine via hydrogenation of an imine
WO2018013686A1 (fr) * 2016-07-12 2018-01-18 Concert Pharmaceuticals, Inc. Idalopirdine deutérée
US10899717B2 (en) 2018-02-28 2021-01-26 Japan Tobacco Inc. 4-methyldihydropyrimidinone compounds and pharmaceutical use thereof

Also Published As

Publication number Publication date
US20160168089A1 (en) 2016-06-16
TW201630881A (zh) 2016-09-01
AR102980A1 (es) 2017-04-05
SG11201704523WA (en) 2017-07-28

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